Natural products and compounds derived from or inspired by natural products make up a large fraction of drug molecules. Traditional synthesis strategies based on recovery from the natural source and chemical synthesis approaches present many challenges associated with the purity, scale, and complexity of the compounds, contributing to the raising costs and reduced number of new drug molecules. The development of scalable manufacturing platforms for natural product synthesis will address many challenges faced between natural product drug discovery and therapeutic application. The engineering of biosynthetic pathways in microbial hosts represents a newer approach to chemical synthesis with exciting potential. However, current approaches in metabolic pathway engineering require a significant investment in time and resources and do not scale with the complexity and breadth represented in natural product biosynthesis pathways. As such, for many natural products of interest, microbial biosynthesis strategies are currently viewed as impossible. The goal of the proposed project is to develop synthetic biology platforms that will dramatically advance the application of cellular biosynthesis strategies to natural product drug discovery, development, and production. The scale and efficiency of manufacturing processes that can be engineered into microbial systems will be transformed through the development of new approaches that will enable the implementation of key biosynthesis process optimization strategies. In particular, the project will pioneer and apply the following approaches: (i) noninvasive and real-time detection of metabolite levels, (ii) closed loop embedded control of biosynthesis system behavior, (iii) active organelle routing supporting biosynthesis specialization and compartmentalization;and (iv) highthroughput screening methods for discovery of new biosynthetic activities within a microbial chassis. The power of these new approaches will be demonstrated by using them to broadly enable biosynthesis across an important natural products family exhibiting diverse pharmacological activities, the benzylisoquinoline alkaloids (BIAs). Taken together, the proposed research will provide a foundation for next generation biosynthesis platforms supporting the synthesis of many natural products for drug discovery and production research. The unique expertise of the P.I. in developing foundational tools for controlling and programming biological function will be key to the successful execution of the proposed project. The project will direct cutting-edge advances in synthetic biology to transforming the way in which we currently approach the discovery, development, and synthesis of therapeutic molecules.

Public Health Relevance

The broad goal of this research is to develop synthetic biology platforms that will dramatically advance cellular biosynthesis strategies for natural product drug discovery, development, and production. By providing scalable manufacturing platforms, the proposed research will transform the way in which the development and manufacturing of drugs is universally approached. These new approaches will be developed and validated on the medicinal benzylisoquinoline alkaoids, an important class of plant secondary metabolites that exhibit diverse activities, including antiviral, antiprotozoan, antibacterial, and antineoplastic activities, and activities for treating cardiovascular and autoimmune diseases.

Agency
National Institute of Health (NIH)
Type
NIH Director’s Pioneer Award (NDPA) (DP1)
Project #
5DP1AT007886-03
Application #
8719021
Study Section
Special Emphasis Panel (ZGM1)
Program Officer
Hopp, Craig
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Stanford University
Department
Biomedical Engineering
Type
Schools of Medicine
DUNS #
City
Stanford
State
CA
Country
United States
Zip Code
94304
Thodey, Kate; Galanie, Stephanie; Smolke, Christina D (2014) A microbial biomanufacturing platform for natural and semisynthetic opioids. Nat Chem Biol 10:837-44
Siddiqui, Michael S; Choksi, Atri; Smolke, Christina D (2014) A system for multilocus chromosomal integration and transformation-free selection marker rescue. FEMS Yeast Res 14:1171-85
Galanie, Stephanie; Siddiqui, Michael S; Smolke, Christina D (2013) Molecular tools for chemical biotechnology. Curr Opin Biotechnol 24:1000-9
Wang, Yen-Hsiang; Wei, Kathy Y; Smolke, Christina D (2013) Synthetic biology: advancing the design of diverse genetic systems. Annu Rev Chem Biomol Eng 4:69-102